The penetration of substances through the skin is important from both toxicological and therapeutic viewpoints. Passive delivery of most compounds across epithelia is limited due to the excellent barrier properties afforded by these epithelia. The stratum corneum is the principal barrier to penetration of most chemicals.
Conventional topical delivery systems are therefore restricted to either substances for local effects or to highly potent, small, lipophilic substances for systemic effects. It is also difficult to deliver ionic and high-molecular-weight drugs in therapeutically sufficient amounts by conventional systems. By way of example, many medical and surgical procedures require local anaesthesia. However, local anaesthetics do not readily penetrate intact skin.
Nitric oxide (NO) is a potent vasodilator synthesised and released by vascular endothelial cells and plays an important role in regulating local vascular resistance and blood flow. Biologically, nitric oxide (NO) is generated from L-arginine via NO synthase enzymes and performs a variety of functions, including vasodilatation and host defence. NO is also manufactured on epithelial surfaces (such as in the mouth and stomach, and on the skin surface) in humans by sequential reduction of nitrate and nitrite. This relies on the synthesis of nitrite by the bacterial reduction of inorganic nitrate present in saliva, mucosal secretions or sweat. Nitrite is further reduced to NO in an acidic environment.
It has previously been discovered that a system that mimics this endogenous mechanism of NO generation, using inorganic nitrite and an organic acid to produce NO on the skin surface, can be used for the transdermal delivery of pharmaceutically active agents.
WO 02/17881 discloses a transdermal delivery system comprising a pharmaceutically active agent and acidified nitrite as an agent to produce local production of nitric oxide at the skin surface. Also disclosed is the use of a barrier consisting of a membrane to allow diffusion of the pharmaceutically active agent and nitrite ions while preventing direct contact of the skin and acidifying agent.